Sedation

Updated: Nov 06, 2018

Author: Arul M Lingappan, MD; Chief Editor: Erik D Schraga, MD

Overview

One of the most important goals of clinicians is patient comfort. When patients present to the emergency department (ED), treating the pain and anxiety that accompany the chief complaint are critical to patient satisfaction and quality of care. Nonetheless, clinicians may underuse sedation, usually from a lack of experience or from unchallenged myths regarding its use.

Sedation is the depression of a patient's awareness to the environment and reduction of his or her responsiveness to external stimulation. This is accomplished along a continuum of sedation levels:

Minimal sedation is equivalent to anxiolysis, that is, a drug-induced relief of apprehension with minimal effect on sensorium.

Moderate sedation is a depression of consciousness in which the patient can respond to external stimuli (verbal or tactile). Airway reflexes, spontaneous ventilation, and cardiovascular function are maintained.

Deep sedation is a depression of consciousness in which the patient cannot be aroused but responds purposefully to repeated or painful stimuli. The patient may not be able to maintain airway reflexes or spontaneous ventilation, but cardiovascular function is preserved.

General anesthesia is a state of unconsciousness; the autonomic nervous system is unable to respond to surgical or procedural stimuli.

Dissociation, which could be considered a type of moderate sedation, is seen when using medications in the phencyclidine group (eg, ketamine). They cause a disconnection between the thalamoneocortical system and the limbic systems, preventing higher centers from receiving sensory stimuli. Like moderate sedation, airway reflexes, spontaneous ventilation, and cardiovascular function are all maintained.[1, 2]

Prior to the administration of medications, clinicians must know the level of sedation required for a given procedure and the appropriate dose of the pharmacologic agent or agents chosen. This determines the equipment that one should have readily available prior to starting the procedure.

Individual patient response to medications can vary; therefore, the clinician can potentially overshoot the desired level of anesthesia. Clinicians must be prepared for this and should have emergency apparatus available in case problems arise.[3]

The medications used during sedation typically have additional beneficial effects, as important as sedation. These actions include the following:

Anxiolysis - Relief of trepidation or agitation with minimal alteration of sensorium

Amnesia - Lapse in memory for a period of time

Analgesia - Relief of pain without an altered sensorium

Sedatives typically have more than one of these actions, although one may predominate. The ideal sedative would exhibit all of the above qualities; most do not. Medications with different qualities are commonly coadministered to compensate for any shortcomings. For example, midazolam is primarily an anxiolytic with some amnestic qualities that is often mixed with fentanyl, primarily an analgesic. When drugs are used as adjuncts, decreasing the dose of each respective drug is important, so as to decrease the incidence of adverse effects.

The medications below are presented according to pharmacologic class. In general, these medications are usually given intravenously when used for procedures in the emergency department (ED), with some exceptions for children (for more information, see Pediatrics, Sedation). Compared with other modes of administration, intravenous medications generally have a quick onset, have a predictable drug absorption, and are titratable. The intravenous route is emphasized in the discussion below.

Sedatives and Analgesics

Benzodiazepines

The benzodiazepines act by stimulating specific benzodiazepine receptors in the CNS. Stimulation of this receptor potentiates the inhibitory effects of gamma-aminobutyric acid (GABA) on GABA-A receptors. This results in chloride influx, hyperpolarization, and decreased ability of the neuron to reach an action potential, producing sedation and anxiolysis. In addition, this class of drugs produces amnesia and has anticonvulsant actions. They have no analgesic properties.

Their most significant adverse effect is respiratory depression and subsequent hypoxemia. Therefore, exercise caution when administering this medication to patients with underlying chronic obstructive pulmonary disease (COPD).[4, 1] Cardiovascular depression, resulting in hypotension with reflex tachycardia, is another adverse effect, but it is not significant at typical doses unless hypovolemia is present or unless it is coadministered with centrally acting analgesics. Be cautious when giving a hepatically metabolized benzodiazepine (eg, midazolam) to a patient with cirrhosis.[4]

Benzodiazepines differ by the methods they can be given, time of onset, action duration, mechanism of metabolism, and presence of active metabolites. As mentioned earlier, their mechanism of action is seen clinically as anxiolysis, amnesia, and sedation; if a particular procedure is painful, these drugs must be given with analgesic agents. In nonintubated patients, the desired effect is found by titration until the desired effect is achieved. Caution must be used in children; they may have a paradoxical disinhibition and increased agitation at low doses.[1] For more information, see Pediatrics, Sedation.

Benzodiazepines include midazolam, lorazepam, and diazepam.

Midazolam is a benzodiazepine with a unique imidazole ring that allows for both lipophilic and hydrophilic properties.[5] When the pH is less than 4, it is water soluble and the chance of pain at the injection site is lowered. Unlike other benzodiazepines, midazolam becomes lipophilic at a pH greater than 4. Midazolam crosses the blood-brain barrier with ease as a lipophilic molecule, producing sedation in less than 5 minutes.

The total dose in adults is 0.02-0.1 mg/kg. The initial pediatric dose is 0.05-0.15 mg/kg IV or IM. The duration of action is about 30 minutes, although sedation may be prolonged in elderly patients. Midazolam is metabolized by the hepatic microsomal system and is not affected by renal failure (caution with cirrhosis).[4]

Midazolam is the fastest acting of its class because of its lipophilic abilities, and it is superior to lorazepam and diazepam in its amnestic effects, making it the ideal benzodiazepine for use in short ED procedures.[1]

Lorazepam is a water-soluble benzodiazepine. The dose range in adults is usually 1-4 mg. The initial pediatric dose is 0.1 mg/kg. It is an intermediate-acting benzodiazepine; its effects begin within 3-5 minutes and peak at 20-30 minutes. The effects of lorazepam generally last 1-4 hours.

Lorazepam has a few advantages over midazolam: first, metabolism occurs by means of conjugation, which makes it more suitable than other benzodiazepines for use in the presence of renal or hepatic failure. Second, lorazepam does not have any active metabolites. Thus, it can be given as a continuous intravenous infusion (0.03-0.1 mg/kg/h) with less concern for adverse effects than an intravenous midazolam drip. For this reason, it is the preferred agent for continuous administration.

Lorazepam's utility in the ED could be for longer-term sedation; for example, patients undergoing mechanical ventilation.[1]

Diazepam, a longer-acting benzodiazepine, was the first benzodiazepine developed for intravenous use. It is insoluble in water and is commercially prepared in propylene glycol. The intravenous dose range for adults is 2-10 mg. The onset of action is relatively rapid, but the duration of action is 2-4 hours. It is metabolized almost exclusively in the liver; therefore, this drug should not be used in patients with cirrhosis. When it is broken down, its metabolites are not only active but possess very long half-lives (ie, 36-90 h). The drug profile of diazepam is not very conducive to procedural sedation.

Barbiturates

Barbiturates are very potent sedatives. Some of the more common uses include induction for endotracheal intubation and ED sedation. They possess primarily sedative properties and some amnestic effects but no analgesic properties. Like benzodiazepines, they are often used as adjuncts to analgesics for painful procedures. Barbiturates should be given with caution to persons with COPD, as they have been shown in early studies to increase the potential for respiratory suppressive effects.[1]

Drugs in the barbiturates class include methohexital and thiopental.

Methohexital is the shortest acting of the barbiturate sedatives, with a rapid onset of action (< 1 min) and a short duration of action (5-10 min). The adult dose for induction is 0.75-1 mg/kg. It also can be used as a sedative for brief procedures, in which case, it is titrated to effect. Adverse effects include hypotension (due to vasodilatation and myocardial depression with reflex tachycardia), which can be more evident in hypovolemia. It should be used with caution in hemodynamically unstable patients, starting off at lower doses (0.5 mg/kg) and titrating up slowly to sedation.[1, 4]

Thiopental is another short-acting barbiturate sedative, lasting about 5-20 minutes. Like methohexital, it is used for induction during intubation and can also be used during brief procedures. The dose is 2-4 mg/kg. The dose should be lowered for critically ill or elderly patients. The main adverse effects include hypotension, which is potentiated by patients who are hypovolemic or critically ill.[4]

Nonbarbiturate sedatives

Nonbarbiturate sedatives have all of the sedative properties of barbiturates. They have gained significant popularity in ED procedural sedation. The two most commonly used (and studied) are propofol and etomidate.

Propofol is an alkyl phenol derivative compound prepared in a 10% lipid emulsion. Originally promoted as an anesthetic induction agent, propofol is also used as a short-acting sedative for bolus administration or continuous infusion. It has a rapid onset of action (< 1 min) and short duration of action (approximately 10 min but is dose-dependent). Clearance of the drug is not affected by renal or hepatic dysfunction, as it has no active metabolites.

Propofol is a respiratory and cardiovascular depressant; these effects have limited its use in the ED in the past, but it has become very popular, particularly for deep procedural sedation.[6, 7, 8, 9] It has been studied in fracture dislocation, incision and drainage, and cardioversion.[9] Propofol can be used in the ED as a sedative for short-term procedures, starting with 1 mg/kg and titrating to effect in increments of 0.5 mg/kg in adults.[6, 5] This also is a very good agent for sedation in patients receiving mechanical ventilation; under these circumstances, it is administered as a continuous infusion starting at 5-10 mcg/kg/min and then titrated to effect.

The total dose given typically ranges from 25-125 mcg/kg/min. It has direct cardiodepressant effects, leading to decreased blood pressure and heart rate. As propofol is a pure sedative/amnestic, an analgesic should be given prior to its administration; giving them simultaneously increases risk for adverse effects.[9, 10]

Blood pressure should be frequently monitored during titration. Patients who have underlying disease (American Society of Anesthesiologists [ASA] Class 3 or 4) are at increased risk for developing hypotension.[9] The suppression of hypoxic respiratory drive is dose-dependent. Patients who need ventilator support are generally older.[9, 11] Propofol is contraindicated in patients with allergies to soybean or eggs.[12]

Etomidate is an imidazole derivative compound with sedative properties. Administered intravenously, etomidate has rapid onset of action (< 1 min) and a short but dose-dependent duration of action (5-8 min). A major feature of this agent is that cardiovascular effects are negligible during deep sedation. It may cause transient neuromuscular twitching that is sometimes confused with seizure activity. One study showed that pretreatment with magnesium sulfate may prevent etomidate-induced myoclonus.[13]

Its major application is induction for endotracheal intubation, especially for patients at risk for hemodynamic compromise. The recommended dose for intubation is 0.3 mg/kg in adults and children, although the dose may be reduced to 0.15 mg/kg in critically ill patients. It can be also be used in procedures as a one-time dose. Etomidate has been shown to depress adrenal cortical function in critically ill patients,[14, 15] but this may not be clinically significant in short-term administration.[16] Because of this effect and because the drug is mixed in propylene glycol, neither titration nor continuous infusion is recommended.

Opioids

Opioids are agents that induce systemic analgesia, some anxiolysis, and mild sedation. They do not induce amnesia of any significance. Opioids are typically coadministered with benzodiazepines for added sedation, anxiolysis, and amnesia. They act by binding to specific opioid receptors in the CNS. They are the class of drugs most commonly used for pain management.

Opioids include morphine, fentanyl, and meperidine.

Morphine is the oldest and most established agent for pain management in the ED. In its intravenous form, it has a rapid onset of action. Its duration of action, however, can be as long as 3-4 hours. The dose is 0.1-0.15 mg/kg (5-10 mg initially for adults), with additional doses as needed. The primary adverse effect is hypotension, explained partially by histamine release. Administering the medication slowly can minimize this effect. Respiratory suppression can also occur, and its risk increases with coadministration of sedative agents.[1]

Fentanyl is a very potent synthetic opioid and one of the commonly used analgesic adjuncts in the ED. It rapidly crosses the blood-brain barrier and thus has a rapid onset of analgesia (< 90 s). However, the serum levels rapidly decline because of tissue redistribution, making the duration of action about 30-40 minutes. It has minimal cardiovascular effects such as hypotension. Respiratory depression is uncommon, but it is potentiated when used in combination with benzodiazepines.

The intravenous dose is 2-3 mcg/kg (50-200 mcg in adults), titrated in 50 to 100-mcg increments. It is the preferred drug for analgesia in short procedures and in cases of trauma with potential hemodynamic compromise.[1] As an analgesic adjunct to continuous sedation, it can be administered as a continuous infusion in doses of 1-3 mcg/kg/h.

Meperidine's duration of action (2-3 h) is intermediate when compared with fentanyl and morphine. Intravenous dosing is 0.5-1 mg/kg initially (35-100 mg for adults). It has an active metabolite, normeperidine, that can lower the seizure threshold, and it becomes problematic in renal failure. It offers no advantage over fentanyl or morphine. It is rarely used in procedural sedation.

Nonopioid analgesic

Ketamine is a dissociative anesthetic and analgesic with a short duration of action. It is unique in that it produces a state in which respiration and airway reflexes are maintained while patients are unaware of their surroundings. At lower doses, patients can respond to simple commands, but they seem to be unaware of painful stimuli. It rarely produces hemodynamic depression.

Ketamine is water soluble and lipophilic. Given intravenously, the onset of action is rapid (causing minimal pain at the injection site), and the duration of action is about 15-30 minutes. The dose recommended is 1-2 mg/kg IV, which typically produces a full dissociative state, though some data suggest that adequate sedation is possible with smaller doses.[17] The emergence reaction (ie, hallucinations developing during recovery from the dissociative state) is one adverse effect. It is more severe in adults and can be attenuated with the administration of a benzodiazepine (eg, midazolam) before recovery.[1]

Ketamine usage has a few adverse effects. Laryngospasm is arguably the most feared adverse reaction. Although laryngospasm usually is manageable with conservative techniques, expertise and equipment must be available to manage the airway in this situation. Ketamine also inhibits catecholamine reuptake at the neuromuscular junction, which leads to slight increases in the heart rate, blood pressure, and cardiac output. In children, ketamine can cause increased salivary and respiratory tract secretions; it can be given with atropine to mitigate this effect (0.01 mg/kg; not to exceed 0.5 mg/dose).

Because of the emergence phenomenon, much of the data on ketamine come from the pediatric population. It is a good choice in children when analgesia and unconsciousness are required (eg, for the repair of a complex facial laceration).[1] In a recent study surveying procedural sedation practices in pediatric EDs, ketamine was by far the most commonly chosen sedation agent for extremity reduction.[18] It is useful in adults, as well.

Ketamine causes bronchial smooth muscle relaxation, making it the preferred drug for sedation/analgesia in patients with asthma.[1] Also, since its cardiovascular effects are minimal, it is another agent to consider for use in hemodynamically unstable patients (eg, induction for intubation).[1] Moreover, it shows promise as a preferred drug in patients with traumatic brain injury, countering former claims of increased intracranial pressure with ketamine usage.[19, 20]

Ketamine has also been used at subdissociative doses (0.1-0.5 mg/kg) as an analgesic in conjunction with sedative-amnestic medications. One study comparing subdissociative-dose ketamine with fentanyl during sedation with propofol showed fewer episodes of hypoxia and hypoventilation with the former.[21]

Inhalation agents

The inhaled anesthetic nitrous oxide, as a 30-70% mixture in oxygen, acts as a sedative and analgesic. It has a rapid onset of action (1-2 min) and a rapid duration of action (5 min). It is thought to act by binding to the opiate receptors in the CNS. Adverse effects include vomiting and hypoxia, if not mixed with an adequate oxygen percentage fraction.

The sedative properties of nitrous oxide are more noticeable clinically than its analgesic properties. Therefore, unless the procedure is a minor one, coadministration with an analgesic is recommended.[22] A scavenging system is often required for its use to prevent environmental air contamination. While some data suggest some utility, particularly in the pediatric population,[23] nitrous oxide is not routinely administered in the ED. For more information, see Nitrous Oxide Administration.

Dexmedetomidine

Dexmedetomidine (Precedex) is a highly selective alpha2-adrenergic agonist that provides sedation, anxiolysis, hypnosis, analgesia, and sympatholysis. It also has opioid-sparing properties. It is indicated for ICU sedation in patients who are mechanically ventilated. It is also indicated for sedation of nonintubated patients prior to and/or during surgical and other procedures.[24]

ICU sedation

Dexmedetomidine is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting by continuous IV infusion for up to 24 hours. It has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue dexmedetomidine prior to extubation.In the randomized, double-blind, multicentre MIDEX and PRODEX trials that studied ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. Patients receiving dexmedetomidine had a higher incidence of hypotension and bradycardia compared with midazolam (20.6% vs 11.6% and 14.2% vs 5.2% respectively).[5]

Clinical practice guidelines by the Society for Critical Care Medicine that include recommendations on sedation in adult patients in the ICU urge the use of light sedation (vs deep sedation) in critically ill, mechanically ventilated adults. The guidelines also recommend the use of either propofol or dexmedetomidine over benzodiazepines for sedation in critically ill, mechanically ventilated adults.[25]

Procedural sedation

Dexmedetomidine is also indicated for sedation of nonintubated patients prior to and/or during surgical and other procedures. The drug has several characteristics that make its use for procedural sedation very appealing. First, it provides little to no respiratory depression.[26] Also, patients are able to follow commands and respond to verbal and tactile stimulus but fall quickly asleep when not stimulated. It does provide some pain relief, like ketamine, but not to the same degree. This makes the use of other analgesics necessary for the more painful procedures. Minimal cardiovascular effects are seen and include mild bradycardia and a decrease in systemic vascular resistance.[27] Onset of action is rapid and the drug’s half-life is approximately 4 minutes after a 10-minute infusion.[28] Dexmedetomidine is 1600 times more selective for alpha2 than alpha1 receptors and provides predictable results.[29]

Approach to Sedation

The therapeutic goals of sedation in the ED must constantly be considered before, during, and after the process to ensure the necessity and adequacy of anesthesia. The clinician must weigh the potential for pain and discomfort of a given procedure with the risks that might be associated with sedative medications. However, clinicians should not withhold needed analgesia or sedation, especially in particularly painful or stressful procedures. Doses can always be adjusted as the clinical situation demands.

Numerous indications exist for sedation; invasive procedures are highly stressful and should at least prompt consideration of sedation. Even minor procedures routinely performed without sedation, such as lumbar puncture, may be facilitated and performed with more patient comfort when sedatives are administered. Rapid-sequence endotracheal intubation in a patient who is not in arrest is another indication for sedation, often used in conjunction with paralytics. If neuromuscular blockers/paralytics are used, adequate sedation is an absolute requirement. An agitated or confused patient who does not respond to reassurance is another candidate for sedation, particularly if the patient has cardiopulmonary compromise that is affected by physiologic stress.

Considerations before and during sedation

Considerations before and during sedation include periprocedural patient assessment, periprocedural fasting, and monitoring.[30]

A patient's preprocedural health status is an important factor to consider before administering any sedative or analgesic. This helps the clinician determine whether to use sedation for a given procedure and determine which pharmacologic agent to use.

Currently, very few outcome-based studies that dictate what clinical parameters to focus on are available. ED clinicians depend on a comprehensive medical and surgical history, vital signs, mental status, and airway and cardiopulmonary assessment. At the current time, no preprocedural diagnostic tests are supported by literature.[30]

The American Society of Anesthesiologists (ASA) developed a physical status classification system to risk-stratify patients receiving sedation for surgical procedures.

Class 1 - A normal healthy patient

Class 2 - A patient with mild disease

Class 3 - A patient with severe disease

Class 4 - A patient with severe disease that is a constant threat to life

Class 5 - A moribund patient who is not expected to survive without the operation

ASA class 3 or higher is proven to be an independent risk factor for adverse outcome in patients undergoing general anesthesia.[31] Procedural sedation in the ED has been studied most extensively in patients who are ASA class 1 and 2. These patients are at low risk for periprocedural and postprocedural complications.[30] Many clinicians would opt not to give sedation to a patient in ASA class 3 or greater, given a risk of morbidity or mortality. Hopefully, this subject will be studied to further streamline periprocedural assessment and the applicability of the ASA physical status classification system to the ED.

Periprocedural fasting has historically been a concern for clinicians because of the suspected risk of aspiration. Most of the data are from patients receiving general anesthesia;[30] in these procedures, airway reflexes are lost and, thus, aspiration risk is increased. Aspiration most commonly occurs during intubation and extubation.[30] Thus, while depth of sedation should be a concern, the idea of preprocedural fasting for procedural sedation is controversial and impractical. The current recommendation from the anesthesia community are 2 hours of fasting for clear liquids and 6 hours for solids.[31] However, in an ED, where the flux of patients is constant and very little control of preprocedural fasting times is possible, these recommendations may not be realistic.

To date, one instance of aspiration involving procedural sedation in the ED has been reported, with no adverse events.[32, 33] This can be explained by the following: (1) In order to aspirate, one must vomit and lose protective airway reflexes, and, with the exception of sedation used in rapid-sequence intubation, this combination is unlikely to happen during procedural sedation, and (2) with the exception of nitrous oxide, procedural sedation is not accomplished in the ED using inhalational agents, which are known to be emetogenic.

Given the lack of solid evidence to support periprocedural fasting times, the academic emergency medicine community does not risk-stratify based on a patient's last meal; instead, they advise clinicians to rely on clinical judgment.[30] The procedural sedation guidelines from the American College of Emergency Physicians (ACEP) state that "recent food intake is not a contraindication for administering procedural sedation and analgesia, but should be considered in choosing the timing and target level of sedation."[30]

Though the risk of aspiration is small, it is real and potentially fatal, and it must be balanced against the patient comfort and safety afforded by procedural sedation. To this end, Green et al recommend a 4-step assessment to minimize aspiration.[34] They first suggest risk stratification of patients based on individual risk. Oral intake is quantified, as is the urgency of the procedure, and a consensus-based opinion is given for the appropriate level of sedation.[34] For instance, a high risk patient who ate a light snack and needs a semi-urgent procedure should receive minimal sedation only. Though this assessment is based on consensus from leading emergency medicine researchers and definitions of certain groups are vague, it gives a general guideline to follow. Of course, no guideline should replace sound clinical judgment.

The clinician must use visual observation to assess the patient's level of consciousness (ie, level of sedation), in conjunction with vital signs, oxygen saturation through pulse oximetry, and cardiac rhythm monitoring. However, these are not enough.

Exhaled carbon dioxide levels may prove very useful in assessing respiratory suppression. End-tidal carbon dioxide concentration (ET CO2) is already a standard assessment tool in the ICU and the OR, but studies in the ED setting are scarce. While pulse oximetry is useful in detecting hypoxemia, it is not useful at detecting the hypercapnia that often precedes hypoxemia in a patient with respiratory suppression. Hypoxia is a late marker of inadequate ventilation.

In a small study of 63 adult patients undergoing procedural sedation breathing room air, desaturation detectable by pulse oximeter usually occured before overt changes in capnometry were identified.[35]

An increase in exhaled CO2 might be the only clue of respiratory compromise. ET CO2 detects respiratory depression earlier than standard practice criteria (ie, clinical markers, oximetry, and hemodynamic monitoring).[36, 37] Another study showed that providing supplemental oxygen via nasal cannula may mask respiratory depression in patients receiving moderate sedation with midazolam and fentanyl.[38] This delay did not result in adverse events, so the clinical significance of this remains unclear.

The bispectral index (BIS) may also be very useful. BIS was once only used by anesthesiologists. Encephalographic wave patterns are used to determine sedation depth, measured on a 100-point scale, 1 being no brain activity and 100 being full alertness. A BIS score below 60 corresponds with a low probability of response to verbal stimuli.[39, 40]

Studies have been performed to validate BIS as a reliable marker for respiratory suppression.[40, 41] One such observational study showed that BIS scores between 70 and 85 provided adequate amnesia and analgesia while minimizing risk of respiratory depression.[40] A follow-up sought to show that knowledge of the BIS value changed clinician behavior.[41] In this prospective randomized study, the incidence of propofol-induced respiratory suppression was decreased when the BIS was known to the clinician. Although the latest recommendations from the ACEP state that "there is insufficient evidence to advocate [the routine use of BIS] in procedural sedation and analgesia", future studies will likely assess its utility.[30]

Sedation route and frequency

Every patient responds differently to dose and type of sedative, and durations of action vary greatly among patients. The patient must be reassessed and the drug readministered as needed. To date, however, no guidelines are put forth in the medical literature.

In the ED, the ideal route of administration is intravenous.[1] Oral and intramuscular absorption may be unreliable and can often be delayed. With intravenous administration, the effect can be assessed fully, since time to peak effect can be predicted with reasonable accuracy. This can allow repeated dosing with much less chance of unexpected deterioration due to drug accumulation.

The intramuscular route may be an attractive alternative to intravenous administration, particularly in children. One study in children showed more effective sedation with intramuscular (using 4 times the IM dose compared to IV), but longer recovery times. Adverse respiratory events (including laryngospasm) did not increase, but the study was underpowered to detect a significant difference.[42] The longer recovery time for intramuscular administration was reproduced in a more recent prospective case series, along with more adverse events.[43] The apparently better efficacy of intramuscular ketamine and ease of administration compared to the intravenous route might be offset by more adverse events and longer recovery times.

Pediatric Considerations

Essentially all the sedatives and analgesics listed above can be used in children. However, the clinician should recognize the differences between children and adults and how that relates to the type of sedation chosen. Differences exist in cognitive abilities and developmental status, respiratory mechanics, airway anatomy, drug metabolism, and toxic dosages. Presedation assessment of a child is very different than that of adults and must adapt to the limited speech and expressive capabilities of children.[44] A child's behavioral state must be assessed before picking an agent, as his or her state may affect the choice of drug and the dose.[44, 45, 46]

Small children have a higher oxygen consumption and lower alveolar volume relative to their weight, making them more susceptible to desaturation and apnea.[22] Moreover, their tongues are larger and they are at increased risk for airway obstruction during moderate or deep sedation.[22] Body composition changes as the child grows, thus altering the distribution of a given medication. Hepatic enzyme systems, plasma concentration of proteins, and renal dynamics all change as the child grows; thus, a guide should be handy to the clinician to accommodate those differences.

Initial dosing and incremental dosing are generally based on weight. Two important considerations are (1) prolonged administration of propofol, which is associated with lactic acidosis (see nonbarbiturate sedatives, propofol in Sedatives and Analgesics); and (2) opiate use in neonates. Opiate clearance is relatively slow in neonates; continuous pulse oximeter monitoring and easy access to airway equipment is strongly recommended, as apnea is a risk.[22] End tidal CO2 monitoring may be useful as well.

Pediatric procedural sedation is being used in a safe and effective manner outside of the academic setting. According to the recent Procedural Sedation in the Community Emergency Department (ProSCED) registry, emergency clinician-directed procedural sedation resulted in successful completion of procedures 99.4% of the time, with complications arising in only 0.6% of cases.[47] Those cases resulted in no significant adverse events and no significant delay in the ED length of stay. A small 2010 study compared the effects of etomidate/fentanyl vs ketamine/midazolam during orthopedic reductions in a pediatric ED.[48] The results indicated that the incidence of adverse reactions to ketamine, including emergence phenomenon, is lower than previously thought.

Fortunately, very severe adverse events are rare in pediatric sedation. However, less severe reactions do occur, and many feel they are underreported because definitions of most adverse events are not standardized. One example is the underreporting of retching in pediatric procedural sedation literature.[49] Prominent experts within the pediatric community recently released a consensus panel to standardize some terminology used in procedural sedation, particularly adverse events and rescue tactics or maneuvers.

The goals of such standardization are to create some established definitions that can fuel more uniform reporting in future publications and give more accurate statistics about adverse events of available medications; and to decrease the occurrence of adverse events by providing a standardized approach at remedying them.[44, 49] Hopefully, such consensus guidelines will translate into the adult literature as well.

For a complete discussion of sedation in the pediatric population, see Pediatrics, Sedation.

Common Sedation Regimens

Benzodiazepines and barbiturates (in combination with an analgesic) are proven to be effective sedative agents. This section focuses on the effectiveness of some of the newer agents when compared with other sedatives and analgesics.

The use of propofol in procedural sedation has been gaining increasing popularity since the 1990s. Many studies have proven its utility as an effective agent. Havel et al showed that the sedation scores and rates of oxygen desaturation between propofol and midazolam were similar within the pediatric population, with equal complication rates.[50] A recent systematic review among adult patients showed no difference in procedural sedation success when comparing propofol and midazolam, and neither agent showed a significant risk of major adverse events.[51]

Another study performed by Miner et al randomized patients into a methohexital/morphine or a propofol/morphine group for ED fracture reduction. The 2 groups were equally efficacious at providing adequate sedation (as measured by the BIS) and had statistically similar rates of respiratory depression.[52] Similar study results were seen in another randomized trial that compared propofol with etomidate and midazolam during cardioversion.[53]

Taylor et al had equally good results when comparing propofol to midazolam/fentanyl in patients who required shoulder reduction, with shorter recovery times in the former group.[8] Some potential limitations to propofol usage do exist. Taylor et al expressed concern over respiratory depression. Clinicians must exercise caution when administering propofol to patients with cardiovascular or pulmonary disease. Under those circumstances, etomidate may be a better alternative.

Etomidate is a safe and efficacious in the ED for procedural sedation. Like propofol, it has a quick onset and short duration of action. In a prospective, double-blinded trial, Burton et al compared midazolam with etomidate for shoulder reduction and found an equal success rate between the 2 groups, with no cardiopulmonary complications.[54] Hunt et al[55] found fast sedation and recovery times with etomidate compared with other medications. Data on etomidate use in children have been limited, but it shows promise when compared to more popular sedatives like midazolam.[56]

The combination of ketamine and propofol, known as ketafol, has become increasingly popular in procedural sedation, partly because of their very divergent adverse event profiles. The combination also satisfies the sedation-amnestic-analgesia balance that is ideal in procedural sedation. It has been defined as a 1:1 mixture of ketamine 10 mg/mL and propofol 10 mg/mL. A prospective evaluation of ketafol showed 96% effectiveness at providing adequate sedation and analgesia.[57] The median recovery time of 15 minutes is comparable to other regimens with short recovery times. Adverse events were minor, and no episodes of hypotension were reported.[57] Ketafol will require larger, more rigorous comparative studies with other regimens to determine its role in procedural sedation.

Antagonists

Flumazenil

Flumazenil is a competitive antagonist of the benzodiazepine class of drugs. The onset of action is within 1-2 minutes after intravenous administration, with peak effects within 10 minutes. The duration of action is dose-related, but it is typically shorter than that of longer-acting benzodiazepines. Repeat dosing may be required. The total recommended dose in adults is 1 mg, which sustains reversal for up to 48 minutes. Flumazenil is generally given in increments of 0.2 mg, titrated to effect. Exercise caution in patients receiving long-term benzodiazepine therapy because it may precipitate acute withdrawal and seizures.[1]

Naloxone

Naloxone is a competitive opiate antagonist. The onset of action following intravenous administration is rapid, with effects appearing within 2-3 minutes. The duration of action is dose-related. The initial dose in adults is 0.4 mg IV. It can be repeated to a total dosage of 2 mg. This antagonist may have shorter duration of action compared with that of the longer-acting opioids. In that case, the patient may need multiple doses. If the patient exhibits signs of respiratory depression before the end of the procedure, 0.1-0.4 mg can be administered for partial reversal. Virtually no adverse effects occur when naloxone is given for procedural oversedation.[1]

Adjuncts

Procedural sedation has many adjuncts that could be used to decrease the dosage requirement of medications or even remove the need for sedation altogether. Hematoma blocks can be used in patients with long bone fractures (classically performed in distal radial fractures). A recent systematic review showed that intraarticular lidocaine injection for long bone fractures resulted in significantly fewer complications when compared to procedural sedation with opiates and benzodiazepines (0.67% vs 13%, respectively), and shorter ED stays.[58]

Digital and regional nerve blocks can be performed with anxiolytic-dose procedural sedation as an alternative to moderate or deep sedation, thus decreasing the potential risks seen with these levels of sedation. This practice can be useful in adults and children.[59]

Summary

In summary, the administration of analgesics and sedatives is an important part of the clinician practice in the ED. Familiarity with available agents allows their appropriate selection and permits the effective and safe use of these drugs. Further study of each of the medications used and the more commonly used combinations will aid in that endeavor.

Gino A Farina, MD, FACEP, FAAEM Professor of Emergency Medicine, Hofstra North Shore-LIJ School of Medicine at Hofstra University; Program Director, Department of Emergency Medicine, Long Island Jewish Medical Center

Gino A Farina, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Society for Academic Emergency Medicine

American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology. 2002 Apr. 96(4):1004-17. [Medline].